We have investigated the dynamics of germinal center (GC) formation in lymphoid tissues following acute SIV infection. SIV induces a marked follicular hyperplasia, associated with an aberrant accumulation of non-proliferating TFH cells within GCs, but with an abundance of cells producing IL-21, demonstrating that the mechanisms involved for these 2 events appear independent. IL-21 stimulated TFH cells are considered a critical element for GC formation, a physiological process that seems dysregulated and excessive during HIV/SIV infection, contributing to lymphoid pathogenesis. However, the data suggest that the kinetics by which such GC are formed may be an important predictor of the host-pathogen equilibrium, as early GC hyperplasia was associated with better control of viral replication. In contrast, monkeys undergoing fast disease progression upon infection exhibited an involution of GCs without local IL-21 production in GCs. These results provide important clues regarding GC-related hyper immune responses in the context of disease progression within various individuals during HIV/SIV infection and may open novel therapeutic avenues to limit lymphoid dysfunction, post infection.

PD176067 is a reversible and selective inhibitor of fibroblast growth factor receptor tyrosine kinase, and was in preclinical development as an angiogenesis inhibitor for the treatment of solid tumors. A 14-day oral toxicity study of PD176067 in young female rats (7 weeks old) was conducted at doses of 2.5, 5, and 10 mg/kg/day (15, 30, and 60 mg/m 2 , respectively). Skeletal changes, and vascular and soft tissue mineralization were observed as primary drug-related toxicities. To determine if these changes are specific to young, rapidly growing animals with increased vascular and osseous development, PD176067 was administered to mature (11 months old) rats. Female rats received PD176067 by gavage for 14 days at doses of 2.5, 5, and 10 mg/kg/day and necropsied on day 15. Clinical signs of toxicity were seen at ≥5 mg/kg and one death occurred at 10 mg/kg. Physeal dysplasia (distal femur, proximal tibia, sternum) occurred in all drug-treated animals and was characterized by dose-related increased thickness of the zones of chondrocyte proliferation and hypertrophy, and marked thickening of the zone of ossification. Cartilage hyperplasia was characterized by proliferation of chondrocytes along margins of the synchondrosis and subperiosteum of sternebrae. Serum phosphorus levels increased 47% and 166% at 5 and 10 mg/kg, respectively. Mineralization of cardiac myocytes, aorta, various arteries, renal tubules, and gastric mucosa and muscularis was seen at 10 mg/kg, and consistent with the presence of calcium-phosphorus deposition. Physeal changes occurred at similar plasma PD176067 exposures in young and mature rats (AUC ≥ 4.83 µg · hr/mL). PD176067 produced morphologically similar lesions in young and adult rats.

No abstract

Granular cell tumors of the reproductive tract in rodents granules with indistinct cell borders and were separated by have been reported primarily in the uterine cervix of mice collagen bundles or smooth muscle cells (Fig. 3). Scattered treated with estrogens.> Spontaneous cervical and vaginal within the mass were foci of perivascular and interstitial granular cell tumors occur rarely in the Fischer rat.' We mononuclear cell infiltrates. Both granular cell tumors were describe histopathologic, immunohistochemical, and ultra-periodic acid-Schiff positive and diastase resistant (Fig. 4) structural features of granular cell tumors in the uterine cer-and stained faintly with Alcian blue. Both tumors stained vix and vagina of two aged Wistar rats.positively for S-l 00 protein. The tumor from rat No. I had Tumor specimens were obtained from animals from a foci that stained positively for neuron-specific enolase. Nei-2-year carcinogenicity study. Rat No.1 was a 11O-week-old ther tumor stained for vim entin, desmin, or actin. Ultravehicle control female Wistar rat. Rat NO.2 was a l l O-week-structural examination of tumor tissue from rat No.2 reold female Wistar rat that had been treated intravenously vealed that cytoplasmic granules were actually large aggregates with a synthetic anticancer chemotherapeutic compound. (approximate average diameter 3 !Lm) of polymorphous maTreatment consisted of once daily dosing for 5 days, followed terial (Fig. 5a). The aggregates contained single membraneby a 23-day recovery period. This regimen was repeated for bound lysosomal bodies of various sizes (approximately 200-six dosing cycles. Vehicle consisted of N,N-dimethylacet-400 nm in diameter) and shapes, with electron-dense amoramide (DMA) in a lactic acid diluent. Neither the test sub-phous cores. Electron-dense bodies were packed together with stance nor vehicle possessed any known estrogenic proper-smaller, moderately electron-dense granular material that had ties.an approximate average diameter of 40 nm (Fig. 5b). CyTissues were fixed in 10% neutral buffered formalin, pro-toplasm also contained scattered profiles of free ribosomes, cessed for light microscopic examination, and stained with mitochondria, and mildly dilated rough endoplasmic retichematoxylin and eosin, Masson's trichrome, Alcian blue, and ulum. Nuclei were peripherally located and round to slightly periodic acid-Schiff. Three-micrometer deparaffinized sec-indented and contained dispersed euchromatin and a single tions were stained by the avidin biotin peroxidase immu-prominent nucleolus. Basal lamina were not seen; however, noperoxidase method as previously described.t' using rabbit a few poorly defined widely distributed cell junctions were polyclonal anti-bovine S-100 protein and neuron-specific observed. enolase (DAKO Corp., Carpinteria, CA), mouse monoclonal Granular cell tumors have been described in seminal vesanti-porcine vimentin (Biogenex, San Ramon, CA), anti-hu-icles and in uteri of 2-year-old untreated Naval Medical Reman desmin (DAKO Corp.), and acti...

The great apes include, in addition to Homo, the genera Pongo (orangutans), Gorilla (gorillas), and Pan, the latter comprising two species, P. troglodytes (chimpanzees) and P. paniscus (bonobos). Adult-onset hypothyroidism was previously reported in 4 individual nonhuman great apes. However, there is scarce information on normal serum thyroid hormone levels and virtually no data for thyroid autoantibodies in these animals. Therefore, we examined thyroid hormone levels and TSH in all nonhuman great ape genera including adults, adolescents, and infants. Because hypothyroidism in humans is commonly the end result of thyroid autoimmunity, we also tested healthy and hypothyroid nonhuman great apes for antibodies to thyroglobulin (Tg), thyroid peroxidase (TPO), and the TSH receptor (TSHR). We established a thyroid hormone and TSH database in orangutans, gorillas, chimpanzees, and bonobos (447 individuals). The most striking differences are the greatly reduced free-T4 and free-T3 levels in orangutans and gorillas vs chimpanzees and bonobos, and conversely, elevated TSH levels in gorillas vs Pan species. Antibodies to Tg and TPO were detected in only 2.6% of adult animals vs approximately 10% in humans. No animals with Tg, TPO, or TSHR antibodies exhibited thyroid dysfunction. Conversely, hypothyroid nonhuman great apes lacked thyroid autoantibodies. Moreover, thyroid histology in necropsy tissues was similar in euthyroid and hypothyroid individuals, and lymphocytic infiltration was absent in 2 hypothyroid animals. In conclusion, free T4 and free T3 are lower in orangutans and gorillas vs chimpanzees and bonobos, the closest living human relatives. Moreover, thyroid autoantibodies are rare and hypothyroidism is unrelated to thyroid autoimmunity in nonhuman great apes.

Certain new fluoroquinolones have high activity against enterococci. Against Enterococcus faecalis (n ‫؍‬ 18), MICs at which 90% of the isolates were inhibited were as follows (in micrograms per milliliter): clinafloxacin, 0.125; CI-990, 0.5; and PD 138312, 0.25 (compared with 1 g/ml for ciprofloxacin and 2 g/ml for ofloxacin). Strains producing ␤-lactamase or that were vancomycin resistant or resistant to high-level gentamicin were not quinolone cross-resistant. The drugs were bactericidal and were unaffected by 50% human serum. Oral efficacies (in milligrams per kilogram of body weight for 50% protective doses) in lethal mouse infections with quinolone-susceptible strains were 4.3 to 24 for clinafloxacin, 7.2 to 39 for CI-990, 7.2 to 76 for PD 138312, and 41 to >100 for ciprofloxacin; when the drugs were given subcutaneously, the order was similar and values ranged from 1.1 to 12.5. Clinafloxacin, CI-990, and PD 138312 may have therapeutic potential in systemic enterococcal infections in humans.Enterococci have gained increasing recognition as primary human pathogens. Resistance to penicillins, aminoglycosides, and glycopeptides (6,13,14,(20)(21)(22) and to quinolones such as ciprofloxacin (18) Frequencies of single-step spontaneous mutations were determined in duplicate by spreading ϳ10 11 CFU onto MuellerHinton agar (Difco Laboratories) containing drugs; colonies were counted after 24 to 72 h of incubation. Multistep resistance selection measured increases in MICs over daily transfers in 5-ml volumes (0.1-ml inoculum harvested from a tube

Idiopathic pulmonary fibrosis (IPF), one of the most severe interstitial lung diseases, is a progressive fibrotic disorder of unknown etiology. However, there is growing appreciation for the role of viral infection in disease induction and/or progression. A small animal model of multi-organ fibrosis, which involves murine gammaherpesvirus (MHV68) infection of interferon gamma receptor deficient (IFNγR-/-) mice, has been utilized to model the association of gammaherpesvirus infections and lung fibrosis. Notably, several MHV68 mutants which fail to induce fibrosis have been identified. Our current study aimed to better define the role of the unique MHV68 gene, M1, in development of pulmonary fibrosis. We have previously shown that the M1 gene encodes a secreted protein which possesses superantigen-like function to drive the expansion and activation of Vβ4+ CD8+ T cells. Here we show that M1-dependent fibrosis is correlated with heightened levels of inflammation in the lung. We observe an M1-dependent cellular infiltrate of innate immune cells with most striking differences at 28 days-post infection. Furthermore, in the absence of M1 protein expression we observed reduced CD8+ T cells and MHV68 epitope specific CD8+ T cells to the lungs—despite equivalent levels of viral replication between M1 null and wild type MHV68. Notably, backcrossing the IFNγR-/- onto the Balb/c background, which has previously been shown to exhibit weak MHV68-driven Vβ4+ CD8+ T cell expansion, eliminated MHV68-induced fibrosis—further implicating the activated Vβ4+ CD8+ T cell population in the induction of fibrosis. We further addressed the role that CD8+ T cells play in the induction of fibrosis by depleting CD8+ T cells, which protected the mice from fibrotic disease. Taken together these findings are consistent with the hypothesized role of Vβ4+ CD8+ T cells as mediators of fibrotic disease in IFNγR-/- mice.

CI-1033 (canertinib) is an irreversible inhibitor of the erbB family of transmembrane tyrosine kinase receptors, including the epidermal growth factor (EGF) receptor. Various inhibitors of the EGF receptor, including CI-1033, have resulted in cutaneous toxicity in humans as a common adverse event. In a chronic toxicity study in rats, CI-1033 produced cutaneous lesions with morphologic characteristics similar to that reported in man. Here the authors describe in detail the dermal changes observed, along with other noteworthy findings of that study. Male and female Wistar rats (15/sex/group) were administered CI-1033 for 27 weeks at 2.5, 5, or 10 mg/kg (15, 30, or 60 mg/m 2 , respectively) by gavage. Control animals (15/sex) received vehicle alone (aqueous 0.5% methylcellulose) in a dose volume of 5 mL/kg. Six animals/sex/dose were included for toxicokinetic evaluations. Skin lesions were the primary drug-related toxicity and occurred at ≥2.5 mg/kg in a dose-dependent fashion. The major gross lesions were papules that evolved into crusts and scales that were first observed in weeks 1 and 3, respectively. Alopecia developed in conjunction with the papular eruptions. Skin changes were most pronounced in females, possibly due to higher drug levels. In week 13, CI-1033 plasma AUC(0-24) values were 527 to 1980 ng·h/mL in males and 844 to 2920 ng·h/mL in females at 2.5 to 10 mg/kg. Microscopic changes could be described as 3 patterns that affected the tail and body (haired skin). Pattern 1 consisted of epidermal changes that started as a superficial, perivascular spongiotic dermatitis with evolving epidermal hyperplasia, scale-crusts, and areas of ulceration. Areas of hyperplasia on the tail were often associated with the development of new hair follicles. Pattern 2 was characterized by a suppurative to pyogranulomatous infundibular folliculitis. Pattern 3 consisted of abnormally oriented hair follicles with malformed hair shafts that were associated with a deeper (isthmic) folliculitis; this correlated with alopecia. Elevations in bone marrow myeloid counts correlated with a peripheral leukocytosis, consistent with inflammatory changes in the dermis. In addition, hepatic cholestasis and epithelial atrophy in the gastrointestinal tract and vagina occurred at ≥2.5 mg/kg. In conclusion, CI-1033 produced cutaneous lesions involving the epidermis and hair follicle, and the morphologic characteristics were similar to that reported in clinical studies with various inhibitors of the EGF receptor. These changes are consistent with pharmacologic inhibition of the EGF receptor in these tissues and demonstrate that the rat can serve as an animal model for investigating the mechanisms for this toxicity.